Medicament delivery systems

ABSTRACT

Described herein are systems, devices, and methods for the delivery of substances to, or the sampling of substances from, a patient using a portable and preferably implantable device. The substances introduced to and/or taken from the patient are preferably fluidic and are driven by a miniature pump, such as a microimpedance pump. A number of design variations are explicitly and implicitly described, such as the use of multiple pumps and multiple reservoirs for containing medicaments. Methods of manufacture of these systems and devices are also described, for instance, using molding, micromachining, or lithographic processes.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. patentapplication Ser. No. 13/491,385, filed Jun. 7, 2012, which claims thebenefit of U.S. provisional patent application Ser. No. 61/494,317,filed Jun. 7, 2011 and U.S. provisional patent application Ser. No.61/562,957, filed Nov. 22, 2011, all of which are hereby incorporated byreference in their entirety as if fully set forth herein.

RELEVANT FIELD

The systems and methods disclosed herein relate generally to portabledrug delivery and sampling devices having impedance pumps.

BACKGROUND

For many diseases, treatment with oral or parenteral medicamentadministration requires a high dose which would lead to side effectsthat would inhibit a therapeutic concentration of the medicament fromreaching diseased tissue. Thus, for such diseases, local medicamentdelivery to the diseased tissue is a desirable objective. It can providehigher concentrations of the medicament to the diseased tissue and allowcontrol of the amount, rate and timing of delivery, which makes localdelivery an option for long-term continuous treatment and potentiallyreduces systemic side effects. However, for some anatomical structures,such as the inner ear, local medicament delivery has special challengesdue to, for example, limited natural points of entry, complexstructures, barriers, and delicate environments. Known deliverymodalities, e.g., systemic, intratympanic, etc., have not adequately oreffectively addressed these challenges. Therefore, there is a need for amedicament delivery system that can provide localized delivery of amedicament.

SUMMARY

Described herein are systems, devices, and methods for the delivery ofsubstances to, or the sampling of substances from, a patient using aportable and preferably implantable device. The substances introduced toand/or taken from the patient are preferably fluidic and are driven by aminiature pump, such as a microimpedance pump. A number of designvariations are explicitly and implicitly described, such as the use ofmultiple pumps and multiple reservoirs for containing medicaments.Methods of manufacture of these systems and devices are also described,for instance, using molding, micromachining, or lithographic processes.

Other systems, methods, features and advantages of the subject matterdescribed herein will be or will become apparent to one with skill inthe art upon examination of the following figures and detaileddescription. It is intended that all such additional systems, methods,features and advantages be included within this description, be withinthe scope of the subject matter described herein, and be protected bythe accompanying claims. In no way should the features of the exampleembodiments in this summary section, or in the following descriptionsections, be construed as limiting the appended claims, absent expressrecitation of those features in the claims.

BRIEF DESCRIPTION OF FIGURES

The details of the systems, devices, and methods described herein, bothas to their structure and operation, can be gleaned in part by study ofthe accompanying figures, in which like reference numerals refer to likeparts. The components in the figures are not necessarily to scale,emphasis instead being placed upon illustrating principles. Moreover,all illustrations are intended to convey concepts, where relative sizes,shapes and other detailed attributes may be illustrated schematicallyrather than literally or precisely.

FIG. 1 is a schematic view depicting an example embodiment of amedicament delivery system.

FIGS. 2A-F are cross-sectional views depicting an example method ofmanufacture of a medicament delivery system.

FIGS. 2G-H are schematic views depicting an example method of securinginlet and/or outlet tubes to the delivery system substrate.

FIGS. 3A-E are cross-sectional views depicting example flowdistributions for medicament exiting a medicament delivery system.

FIGS. 4A-B depict another example embodiment of a medicament deliverysystem.

DETAILED DESCRIPTION

The detailed description set forth below in connection with the appendeddrawings is intended to describe various example embodiments and is notintended to represent the only embodiments that may be practiced.

In the following section, numerous examples and example embodiments aredescribed. These embodiments are not described as rigid alternatives,but are rather intended to illustrate the broad scope andinterchangeability of the systems, devices, and methods describedherein. Thus, any feature, element, step, or aspect of one embodimentcan be added to or substituted within any other embodiment describedherein.

An example embodiment of a medicament delivery system 10 is shown inFIG. 1. Generally, the delivery system 10 is intended to be used todeliver a medicament into the inner ear for the treatment of inner earand/or vestibular system disorders (e.g., tinnitus, SNHL, presbycusis,meniere's disease, etc.). While the embodiments described herein will bedone so generally with regard to inner ear delivery, it should beunderstood that these embodiments can be used to deliver substances toany desired tissue or anatomical structure, including but not limited tointrathecal delivery (e.g., for pain management) and intraoculardelivery. Likewise, the delivery system can be used to deliver anydesired substance, drug, medicament, or therapeutic, including but notlimited to cancer therapeutics and insulin.

In the example embodiment of FIG. 1, the delivery system 10 can beimplanted in the mastoid portion of the temporal bone. In an exampleimplantation procedure, a pocket can be formed in the mastoid bone forinsertion of the delivery system 10. Holes can be drilled to provideaccess to the scala tympani for the delivery system 10. In anotherexample embodiment, the delivery system 10 can be implanted using apostauricular mastoidomy or posterior tympanotomy. The delivery system10 can also be configured to lie outside the body and deliver asubstance through a catheter or subcutaneously through a needle.Alternatively, the delivery system 10 can lie outside the body andsample body fluids through a catheter or subcutaneously through aneedle. In yet another example, the delivery system 10 can lie outsidethe body and deliver or sample substances through the dermis.

The delivery system 10 includes a substrate (or body) 12, pump 16 andtubing that can be manufactured from biocompatible polymeric materials(including, but not limited to, silicone, PDMS, PEEK, PTFE andPolysulfone (PSU), other fluoropolymers, PVDF, parylene, polyurethane,polysulphone, polyolefin, polyvinyl chloride, polypropylene,polycarbonate, and PMMA), metallic materials (including, but not limitedto, nickel, titanium, and any alloys thereof (e.g., Ti6A14V), stainlesssteel, and chromium), ceramics (including, but not limited to, zirconiaand alumina), or combinations of the same.

In an example embodiment, the substrate 12 can include a pump chamber 14which houses a pump 16 for circulating fluid through the delivery system10. Pump 16 preferably utilizes a mismatch in impedance to drive flowand can be embodied by a compressible section or movable wall coupled ateither end to wave reflection sites or locations where pressure waveenergy is reflected. Here, pump 16 is an impedance pump enclosed withinsubstrate 12. Pump 16 can be manufactured from one or more materials andcan assume any desired shape. In this example, pump 16 is made fromsilicon and is rectangular. In embodiments where pump 16 is manufacturedfrom two or more materials, the first material can have a firstimpedance and the second material can have a second impedance, differentfrom the first. Of course, any number of materials having differentimpedances can be used. Further examples of pump 16 can be, but are notlimited to, those pump configurations and geometries described in U.S.Pat. Nos. 6,254,355, 6,679,687, 7,387,500, 7,163,385 and U.S. PatentApplication Publication Nos. 2007/0177997 and 2011/0125136. Every patentand published application in the preceding sentence is expresslyincorporated herein by reference for all purposes.

Here, pump 16 has a longitudinal axis L and a transverse (or lateral)axis T. An activation element 18 (e.g., a magnet) can be disposed on asurface of substrate 12, preferably a surface of a thin wall or membraneopposite pump chamber 14. Activation element 18 is adapted to activateand/or instigate the mechanism that causes the pumping action, which inthis embodiment is the movement of the thin wall underlying element 18.Activation element 18 can be a piezoelectric, electromagnetic, ormagnetostrictive device, to name a few. Activation element 18 preferablyinterfaces with a control device, which can also be a portable (e.g.,wearable, implantable, or handheld) device located in proximity withdelivery system 10. The control device (not shown) can generate apermanent or variable magnetic field that interfaces with, e.g., amagnetic activation element 18 and causes that activation element tomove. The control device is preferably programmable and adjustable basedon user input. In one example embodiment, the control device hason-board electronics such as power management, frequency synthesizer,controller, communication links, and a battery.

The device 10 itself may be implanted subcutaneously or worn externallywith the drug perfusion tubing extending into the patient. In anotherexample embodiment, the device functions as an in hospital deliveryplatform for drug perfusion through a venous or arterial catheter placedin the patient. In another embodiment device 10 functions in combinationwith a cochlear implant providing both stimulation and therapeutictreatments.

In the instance where the geometry of the ends of channels 20, 24leading into pump chamber 14 are the same, then magnet 18 is preferablydisposed at a position longitudinally offset from the central transverseaxis T of pump chamber 14. This asymmetry leads to the addition ofpressure waves within chamber 14 that in turn creates the pumping effect(see, e.g., the incorporated U.S. Pat. No. 7,163,385). The geometry ofthe ends of channels 20, 24 leading into pump chamber 14 can also bedifferent, sized in the appropriate manner to allow activation element18 to be centrally placed along axis T.

A first channel 20 is disposed in substrate 12 and has a first opening51 in fluid communication with pump 16 and a second opening 52 in fluidcommunication with an inlet tube 22. Here, openings 51 and 52 are alsolocated at opposite terminal ends of channel 20. A second channel 24 isdisposed in substrate 12 and has a first opening 53 in fluidcommunication with pump 16 (at an end of pump 16 opposite opening 51 offirst channel 20) and a second opening 54 disposed in fluidcommunication with an outlet tube 26. Here, openings 53 and 54 are alsolocated at opposite terminal ends of channel 24. First and secondchannels 20, 24 define a fluid path through substrate 12 for fluid beingpumped by the pump 16. The cross-sectional area of the channels 20, 24can be the same or different from each other, but in either case aresubstantially less than the transverse cross-sectional area of pump 16.

Delivery system 10 can be used with multiple pumps. These additionalpumps can be used to deliver different drugs (e.g., to allow thedelivery of drug combinations or drug cocktails), or used in a cascadedor additive configuration (e.g., to increase the flow rate of thepumping mechanism with system 10). In another embodiment, one or morepumps are used to draw fluid out of a liquid reservoir to combine drugsor drug components. In another embodiment, delivery system 10 contains amixer utilizing an unsteady output of a pump to combine drugs or drugcomponents.

Although the term “delivery system” is used, it should be noted that inall of the embodiments described herein, the pump can be used with theprimary intent to deliver a foreign substance into the patient, or withthe primary intent to extract a substance from the patient (such asblood for diagnostic purposes). In embodiments where a fluid circuit isused to both pass a substance into the patient and extract a substancefrom the patient, those of skill in the art will readily recognize thatthe pump accomplishes both a delivery and extraction function. In FIG.1, a single pump 16 accomplishes both functions, but system 10 can beconfigured with dedicated pumps where one or more pumps primarily (orexclusively) deliver a substance to the body and one or more differentpumps primarily (or exclusively) extract a substance from the body.

Drug perfusion tubing in the form of inlet and outlet tubes 22, 26 canextend laterally from substrate 12 with terminal ends coupled inproximity to each other or coupled to an interface component 28 (e.g., aconnector). For instance, the terminal ends of the tubes 22, 26 on thepatient-side can be configured or molded as a single dual lumen tube.Interface component 28 can be implanted into the inner ear (e.g., via acochleostomy), allowing perilymph to circulate through tubes 22 and 26,channels 20 and 24, and pump 16. Interface component 28 can also besecured to the scala tympani with an adhesive or a graft. While tubes22, 26 are described as “inlet” and “outlet” tubes in the exampleembodiment, those of skill in the art will understand that suchterminology is for reference only, and that each tube can act as aninlet or an outlet depending on the direction of circulation of fluidthrough delivery system 10. Tubes 22, 26 can be manufactured from anydesired metal, metallic alloy, or polymeric material (e.g., PEEK). Oneor more sheaths (not shown) can be used to cover each of tubes 22, 26,for example, to prevent kinking of tubes 22, 26 or accommodate potentialdisplacement of delivery system 10 within the mastoid bone. One sheathcan cover both tubes 22, 26 or separate sheaths can cover each tube 22,26 alone.

A sensor (not shown) can also be included along inlet tube 22 or firstchannel 52 and used to analyze the fluid sampled by the system 10.Alternatively (or additionally), the sensor (or the fluid beingdelivered by system 10).

In an example embodiment, one or more reservoirs 30 are formed insubstrate 12 for containing a substance, e.g., a medicament, adiagnostic agent, etc. Reservoir 30 can be in fluid communication withfirst channel 20 and/or second channel 24 such that the fluidcirculating through delivery system 10 contacts the medicament containedin reservoir 30. Reservoir 30 can be in fluid communication with firstchannel 20 and/or second channel 24 such that fluid does not circulatethrough delivery system 10 yet contacts the medicament contained inreservoir 30. A plurality of reservoirs 30 can be in disposed insubstrate 12. In such embodiments, reservoirs 30 can be disposed inseries or parallel along a channel. Examples of such arrangements aredescribed in the incorporated U.S. Patent Application Publication2011/0125136.

FIG. 4A is a top down view of another example embodiment of deliverysystem 10 where multiple reservoirs 30 are present. FIG. 4B is across-sectional view taken along line 4B-4B of FIG. 4A. Here, fourreservoirs are present and immediately adjacent channel 24. Medicament40 in the form of a solid pill-like element is present within eachreservoir 30, where one type of medicament 40-1 is in two reservoirs andanother type of medicament 40-2 is in the other two reservoirs. Itshould be noted that system 10 can be an integrated (or monolithic)device, or can be modular with, for instance, pump 16 in one module andreservoir 30 in a separate connectable module. Such a configurationwould allow for easy replacement of the medicament.

Reservoirs 30 can also be piggy-backed on each other, such that pumpedfluid will contact a substance in a first reservoir, and that reservoirwill empty (or the substance will be exhausted) before fluid contactsthe same or a different substance in a second reservoir. In anotherembodiment, the terminal ends of the tubes 22, 26 are coupled to twoseparate interface components, for example, to allow outlet tube 26 tobe located in the tissue of interest and to allow inlet tube 22 to becoupled to a liquid reservoir containing, e.g., a liquid formulated drugor a carrier fluid for a drug in solid form located in reservoir 30.

The medicament contained in any reservoir 30 can be a solid formulation(e.g., a monolithic pill, particulates, etc.), a gel formulation (withor without a suspension), a liquid formulation, a slurry formulation,and the like. Example medicaments which can be included in the deliverysystem 10 are nomifensine and dexmethasone. However, those of skill inthe art will understand that other medicaments can be utilized dependingon the therapeutic purpose of the delivery system 10. A morecomprehensive (but non-exhaustive) list is provided in the “Substancesand Applications” section.

The medicament is preferably formulated to prevent portions of themedicament from breaking off and occluding any portion of system 10,particularly channels 20, 24 and/or tubes 22, 26. For example, themedicament can be disposed in a polymeric matrix which maintainsstructural integrity while in contact with the fluid circulating throughdelivery system 10. A physical safeguard can also be used to preventpartial or complete occlusion. For instance, the medicament can bedisposed in a semi-permeable membraneous coating, which can allow fordiffusion of the fluid and the dissolved medicament, but prevent largeparticles of medicament from passing through. Alternatively (oradditionally), a molecular sieve can be used as a filter that allowsdiffusion of the fluid and the dissolved medicament, but prevents largeparticles of medicament from passing through.

The main body of system having substrate 12 is preferably small enoughto be implanted without difficulty. In one example, which is providedfor illustrative purposes only and is not intended to be limiting, thedimensions of the main body of system 10 (without the perfusion tubing)is 5 mm by 20 mm by 20 mm, although both smaller and larger sizes arepossible. The perfusion tubes each preferably have a diameter of lessthan 1 mm, although larger sizes can be used. When used to treatdiseases of the inner ear, e.g., tinnitus, the preferred depth ofimplantation into the scala tympani is less than 0.5 mm.

FIGS. 2A-F depict an example embodiment of a manufacturing process for adelivery system 10. This embodiment generally relates to a two layersystem, although one of ordinary skill in the art will readily recognizethat three or more layers can be used, depending on the complexity ofthe system, the number of pumps, reservoirs, sampling wells, channels,etc.

In FIGS. 2A-B, a first layer 32 and a second layer 36 of substrate 12are provided. Layers 32 and 36 can be formed or molded with theappropriate elements therein. This can be done by first creating a moldwith the positive impressions of the elements thereon, such as throughmicromachining (e.g., soft lithography) or photolithography. Layers 32and 34 will then be formed with negative impressions of those elementstherein. For layer 32, this includes a chamber for magnet 18, reservoir30, and a vertical channel 34, while for layer 36, this includes thepump chamber 14 (present in this stage as an elongate recess), and firstand second elongate channels 20, 24 (not shown). The formation of layers32, 36 can also be done by micromachining or photolithography to etch orcarve the elements directly into layers 32, 36.

Magnet 18 is coupled to (or seated in) layer 32 after formation themagnet chamber. Afterwards, the magnet chamber can be filled withsilicon. Beneath magnet 18 is a thin wall or membrane that can bedisplaced to generate the pumping forces. As shown in FIG. 2A, avertical channel 34 is present to create a fluid path to/from reservoir30. FIG. 2C depicts a reservoir plug 38.

FIG. 2D depicts a medicament 40 disposed in reservoir 30. In thisexample embodiment, medicament 40 is a solid pellet which sits inreservoir 30 and abuts an open end of vertical channel 34. FIG. 2E showsreservoir plug 38 coupled to first layer 32 to seal medicament 40 inreservoir 30. Plug 38 can be bonded to first layer 32 by plasmatreatment, curing of first layer 32, or through the use of an adhesive.In another example embodiment, plug 38 can be molded into first layer32. In yet another example embodiment, plug 38 can be a resealableseptum which covers reservoir 30 but allows for re-filling, e.g., by aneedle injecting a medicament into reservoir 30.

FIG. 2F shows first layer 32 coupled to the second layer 36. First layer32 forms a cover or roof to second layer 36, enclosing the elongaterecess to form pump chamber 14 with the thin pump chamber wall presentin layer 32. The elongate channels are also covered to fully enclosethem (with the exception of the open ends through which fluid flows). Inan example embodiment, layers 32, 36 are bonded by 02 plasma treatmentand a subsequent bond curing period in an oven at 80° C. In anotherexample embodiment, layers 32, 36 can be bonded through thermaltreatments at 80° C. by adjusting a ratio of a curing agent in a mixtureused to fabricate layers 32, 36. In yet another example embodiment,layers 32, 36 are sealed using UV ozone treatment or any other treatmentwhich hydrophilizes the surface of silicone. In yet another exampleembodiment, layers 32, 36 are bonded using an adhesive, e.g., uncuredPDMS. In still another example embodiment, system 10 is hermeticallysealed to prevent the intrusion of bodily fluids.

An overmolding process is preferably used to secure the inlet and outlettubes 22, 26 with respect to channels 20, 24. FIGS. 2G-H depict anexample method used in the securement of tubes 22, 26 with respect tosubstrate 12 for a similar but alternate layout to system 10. In thislayout, reservoir 30 is located laterally offset from channel 24 and iscoupled to channel 24 by way of two feeder channels 55 and 56, eachhaving a cross-sectional dimension less than channel 24. This layout canallow for less concentrated doses.

Preferably, after first layer 32 is coupled to second layer 36, tubes22, 26 are press-fit into openings 60, 61 for channels 20, 24,respectively. FIG. 2G shows the press-fitting insertion of tube 22 intoopening 60 and along a length of channel 20. An adhesive can be used tofurther secure the coupling of tubes 22, 24 to substrate 12 afterpress-fitting.

After both tubes are inserted, an overmolding process can then be usedto encapsulate and fully secure tubes 22, 26 to substrate 12. Uncuredsilicone is poured into a mold holding tubes 22, 26 in the substrate 12and also holding layers 32, 36 together. A priming solution can be usedto increase bond strength between tubes 22, 26 and substrate 12. Thisassembly can then be baked in an oven (e.g., at 80° C.) and cured. Theovermolding process adds an overmolded portion 58 to the length ofsubstrate 12 and surrounds (or encapsulates) and stabilizes tubes 22, 26and layers 32, 36. The overmolding process can be followed byapplication of an adhesive to tubes 22, 26 to further secure them tosubstrate 12. In another example embodiment, tubes 22, 26 are moldedinto first layer 32 or second layer 36, or one tube is molded into firstlayer 32 and the other tube is molded into second layer 36.

FIGS. 3A-E show an example embodiment of medicament delivery by deliverysystem 10. In FIG. 3A, fluid (e.g., perilymph) circulating throughdelivery system 10 contacts medicament 40. For example, as the fluidenters delivery system 10, the fluid can push up through verticalchannel 34 and contact medicament 40, which allows medicament 40 todissolve or disperse into the fluid. As shown in FIG. 3B, prolongedcontact between the fluid and medicament 40, such as when pump 16 isinactive, can allow more of medicament 40 to dissolve into the fluid.Delivery system 10 can include valves to restrict flow during periods ofpump inactivity. Multiple valves can be used. One or more valves can beplaced before or after the pump along channel 20 and/or 24. One or morevalves can also be placed between reservoir 30 and channels 20 or 24(e.g., valves in one or more of feeder channel 55, feeder channel 56,and vertical channel 34). The valves can be off-the-shelf or custombuilt. The valves can be micro-machined, or fabricated in MEMS,multi-leaflet (e.g., bi-leaflet), check, or pincher-type, to name a few.

FIG. 3C shows a displacement of the dissolved medicament 40 when pump 16is activated, e.g., by passing an external actuator (magnet) over magnet18. When this occurs, magnet 18 on pump 16 moves the wall on which it ismounted and compresses the pump chamber to push fluid through deliverysystem 10. Vibrational waves travel along pump 16 and bounce off aninterface between pump 16 and channels 20, 24, due to the rapid changein surface area between the cross-sectional area of pump chamber 14 andthe cross-sectional area of channels 20, 24. Changing location of magnet18 on axis L of pump 16 and/or changing the frequency of oscillations ofpump 16 can increase/decrease, or even reverse direction of, fluid flow.FIG. 3D shows that while pump 16 is activated, the fluid can be pushedpast vertical channel 34 and less fluid can contact medicament 40. Thus,when pump 16 is inactive, a “dose” of medicament 40 can be allowed todissolve into the fluid, as shown in FIG. 3E.

In one example method of delivery, the fluid channels are allowed tofill with the drug and, while the pump remains inactive, the drugspreads diffusely as depicted in FIGS. 3A-B. This can be referred to asmode one. Once the effective dose has been reached, determined either bytime or the presence of a sensor, pump 16 is activated and the drug iswashed out with the fluid transitioning through the channels, asdepicted in FIGS. 3C-D. This can be referred to as mode two. After thisthe pump is turned off again (or made inactive) as shown in FIG. 3E. Thecombination of modes one and two result in the delivery of the effectivedose.

Substances and Applications

The substances that can be used with delivery system 10, as well as theapplications in which system 10 can be used, are very broad. Asdescribed in US Patent Application Publication 2009/0209945, there arenumerous circumstances in which it can be desirable to deliver drugs orother agents in a tissue-specific manner, on an intermittent orcontinuous basis and using implantable drug delivery systems such asthose described herein, to treat a particular condition. Disorders ofthe middle and inner ear can be treatable using the systems and methodsdescribed herein. Examples of middle and inner ear disorders include(but are not limited to) autoimmune inner ear disorder (AIED), Meniere'sdisease (idiopathic endolymphic hydrops), inner ear disorder associatedwith metabolic imbalances, inner ear disorder associated withinfections, inner ear disorder associated with allergic or neurogenicfactors, blast injury, noise-induced hearing loss, drug-induced hearingloss, tinnitus, presbycusis, barotrauma, otitis media (acute, chronic orserious), infectious mastoiditis, infectious myringitis, sensorineuralhearing loss, conductive hearing loss, vestibular neuronitis,labyrinthitis, post-traumatic vertigo, perilymph fistula, cervicalvertigo, ototoxicity, Mal de Debarquement Syndrome (MDDS), acousticneuroma, migraine associated vertigo (MAV), benign paroxysmal positionalvertigo (BPPV), eustachian tube dysfunction, cancers of the middle orinner ear, and infections (bacterial, viral or fungal) of the middle orinner ear. Degenerative ocular disorders can also be treatable using thesystems and methods described herein. Examples of such degenerativeocular disorders include (but are not limited to) dry maculardegeneration, glaucoma, macular edema secondary to vascular disorders,retinitis pigmentosa and wet macular degeneration. Similarly,inflammatory ocular diseases (including but not limited to birdshotretinopathy, diabetic retinopathy, Harada's and Vogt-Koyanagi-Haradasyndrome, iritis, multifocal choroiditis and panuveitis, pars planitis,posterior scleritis, sarcoidosis, retinitis due to systemic lupuserythematosus, sympathetic ophthalmia, subretinal fibrosis, uveitissyndrome and white dot syndrome), ocular disorders associated withneovascularization (including but not limited to age-related maculardegeneration, angioid streaks, choroiditis, diabetes-related irisneovascularization, diabetic retinopathy, idiopathic choroidalneovascularization, pathologic myopia, retinal detachment, retinaltumors, and sickle cell retinopathy), and ocular infections associatedwith the choroids, retina or cornea (including but not limited tocytomegalovirus retinitis, histoplasma retinochoroiditis, toxoplasmaretinochoroiditis and tuberculous choroiditis) and ocular neoplasticdiseases (including but not limited to abnormal tissue growth (in theretina, choroid, uvea, vitreous or cornea), choroidal melanoma,intraocular lymphoma (of the choroids, vitreous or retina),retinoblastoma, and vitreous seeding from retinoblastoma) can betreatable using the devices and methods described herein.

Further examples of conditions that can be treatable using the devicesand methods described herein include, but are not limited to, thefollowing: ocular, inner ear or other neural trauma; disorders of theauditory cortex; disorders of the inferior colliculus (by surfacetreatment or injection); neurological disorders of the brain on top ofor below the dura; chronic pain; hyperactivity of the nervous system;migraines; Parkinson's disease; Alzheimer's disease; seizures; hearingrelated disorders in addition to those specified elsewhere herein;nervous disorders in addition to those specified elsewhere herein;ophthalmic disorders in addition to those specified elsewhere herein;ear, eye, brain disorders in addition to those specified elsewhereherein; cancers in addition to those specified elsewhere herein;bacterial, viral or fungal infections in addition to those specifiedelsewhere herein; endocrine, metabolic, or immune disorders in additionto those specified elsewhere herein; degenerative or inflammatorydiseases in addition to those specified elsewhere herein; neoplasticdiseases in addition to those specified elsewhere herein; conditions ofthe auditory, optic, or other sensory nerves; sensory disorders inadditions to those specified elsewhere herein; conditions treatable bydelivery of drug to the vicinity of the pituitary, adrenal, thymus,ovary, testis, or other gland; conditions treatable by delivery of drugto the vicinity of the heart, pancreas, liver, spleen or other organs;and conditions treatable by delivery of drug to specific regions of thebrain or spinal cord.

The preceding identification of conditions is not intend to beexhaustive. Drug delivery systems and devices according to theembodiments described herein can be used to deliver one or more drugs toa particular target site so as to treat one or more of the conditionsdescribed above, as well as to treat other conditions. Drugs that can bedelivered using the embodiments described herein include, but are notlimited to, the following: antibiotics (including but are not limited toan aminoglycoside, an ansamycin, a carbacephem, a carbapenum, acephalosporin, a macrolide, a monobactam, and a penicillin); anti-viraldrugs (including but not limited to an antisense inhibitor, fomiversen,lamivudine, pleconaril, amantadine, and rimantadine); anti-inflammatoryfactors and agents (including but not limited to glucocorticoids,mineralocorticoids from adrenal cortical cells, dexamethasone,triamcinolone acetonide, hydrocortisone, sodium phosphate,methylprednisolone acetate, indomethacin, and naprosyn); neurologicallyactive drugs (including but not limited to ketamine, caroverine,gacyclidine, memantine, lidocaine, traxoprodil, an NMDA receptorantagonist, a calcium channel blocker, a GABA_(A) agonist, an Ε2δagonist, a cholinergic, and an anticholinergic); anti-cancer drugs(including but not limited to abarelix, aldesleukin, alemtuzamab,alitretinoin, allopurinol, altretamine, amifostine, anastrolzole,anti-hormones such as Arimidex, azacitidine, bevacuzimab, bleomycin,bortezomib, busulfan, capecitabine, carboplatin, carmustine,chlorambucil, cisplatin, cyclophosphamide, cyclosporine, darbepoetin,daunorubicin, docetaxel, doxorubicine, epirubicin, epoetin, etoposide,fluorouracil, gemicitabine, hydroxyurea, idarubicin, imatinib,interferon, letrozole, methotrexate, mitomycin C, oxaliplatin,paclitaxel, tamoxifen, taxol and taxol analogs, topothecan, vinblastineand related analogs, vincristine, and zoledronate); fungicides(including but not limited to azaconazole, a benzimidazole, captafol,diclobutrazol, etaconazole, kasugamycin, and metiram); anti-migrainemedication (including but not limited to IMITREX); autonomic drugs(including but not limited to adrenergic agents, adrenergic blockingagents, anticholinergic agents, and skeletal muscle relaxants);anti-secretory molecules (including but not limited to proton pumpinhibitors (e.g., pantoprazole, lansoprazole and rabprazole) andmuscarinic antagonists (e.g., atropine and scopalomine)); centralnervous system agents (including but not limited to analgesics,anti-convulsants, and antipyretics); hormones and synthetic hormones inaddition to those described elsewhere herein; immunomodulating agents(including but not limited to etanercept, cyclosporine, FK506 and otherimmunosuppressant); neurotrophic factors and agents (factors and agentsretarding cell degeneration, promoting cell sparing, or promoting newcell growth); angiogenesis inhibitors and factors (including but notlimited to COX-2 selective inhibitors (e.g., CELEBREX), fumagillin(including analogs such as AGM-1470), and small moleculesanti-angiogenic agents (e.g., thalidomide)); neuroprotective agents(agents capable of retarding, reducing or minimizing the death ofneuronal cells) (including but not limited to N-methyl-D-aspartate(NMDA) antagonists, gacyclidine (GK11), and D-JNK-kinase inhibitors);and carbonic anhydrase inhibitors (including but not limited toacetazolamide (e.g., DIAMOX), methazolamide (e.g., NEPTAZANE),dorzolamide (e.g., TRUSOPT), and brinzolamide (e.g., AZOPT)).

In at least some embodiments, an implanted drug delivery system such asis described herein is used to deliver a drug (including but not limitedto one or more of the drugs listed above) as a pure drug nanoparticleand/or microparticle suspension, as a suspension of nanoparticles and/ormicroparticles formed from drug formulated with binders and otheringredients to control release, or as some other type of nanoparticle-and/or microparticle-bound formulation. Nanoparticle- and/ormicroparticle-based delivery is advantageous in closed loop embodimentsby allowing drug-containing particles to circulate within the closedloop as a solid suspended in the vehicle while delivering the desiredtherapeutic dose to the target tissue through the semi-permeablemembrane or hollow fiber. Nanoparticle- and/or microparticle-bounddelivery also offers the advantage of maintaining drug stability andavoiding loss of drug to polymeric components that can be encountered ina fluid pathway.

Many diseases and disorders are associated with one or more ofangiogenesis, inflammation and degeneration. To treat these and otherdisorders, the embodiments disclosed herein can permit delivery ofanti-angiogenic factors; anti-inflammatory factors; factors that retardcell degeneration, promote cell sparing, or promote cell growth; andcombinations of the foregoing.

Diabetic retinopathy is characterized by angiogenesis. At least someembodiments contemplate treating diabetic retinopathy by implantingdevices delivering one or more anti-angiogenic factors eitherintraocularly, preferably in the vitreous, or periocularly, preferablyin the sub-Tenon's region. It can also be desirable to co-deliver one ormore neurotrophic factors either intraocularly, periocularly, and/orintravitreally.

Uveitis involves inflammation. At least some embodiments contemplatetreating uveitis by intraocular, vitreal or anterior chamberimplantation of devices releasing one or more anti-inflammatory factors.Anti-inflammatory factors contemplated for use in at least someembodiments include, but are not limited to, glucocorticoids andmineralocorticoids (from adrenal cortical cells).

Retinitis pigmentosa is characterized by retinal degeneration. At leastsome embodiments contemplate treating retinitis pigmentosa byintraocular or vitreal placement of devices secreting one or moreneurotrophic factors.

Age-related macular degeneration (wet and dry) involves bothangiogenesis and retinal degeneration. Embodiments described herein canbe used to deliver one or more neurotrophic factors intraocularly,preferably to the vitreous, and/or one or more anti-angiogenic factorsintraocularly or periocularly, preferably periocularly, most preferablyto the sub-Tenon's region.

Glaucoma is characterized by increased ocular pressure and loss ofretinal ganglion cells. Treatments for glaucoma contemplated in at leastsome embodiments include delivery of one or more neuroprotective agentsthat protect cells from excitotoxic damage. Such agents include, but arenot limited to, N-methyl-D-aspartate (NMDA) antagonists and neurotrophicfactors. These agents can be delivered intraocularly, preferablyintravitreally. Gacyclidine (GK11) is an NMDA antagonist and is believedto be useful in treating glaucoma and other diseases whereneuroprotection would be helpful or where there are hyperactive neurons.Additional compounds with useful activity are D-JNK-kinase inhibitors.

Neuroprotective agents can be useful in the treatment of variousdisorders associated with neuronal cell death (e.g., following soundtrauma, cochlear implant surgery, diabetic retinopathy, glaucoma, etc.).Examples of neuroprotective agents that can be used in at least someembodiments include, but are not limited to, apoptosis inhibitors,caspase inhibitors, neurotrophic factors and NMDA antagonists (such asgacyclidine and related analogs).

At least some embodiments can be useful for the treatment of ocularneovascularization, a condition associated with many ocular diseases anddisorders and accounting for a majority of severe visual loss. Forexample, contemplated is treatment of retinal ischemia-associated ocularneovascularization, a major cause of blindness in diabetes and manyother diseases; corneal neovascularization; and neovascularizationassociated with diabetic retinopathy, and possibly age-related maculardegeneration.

One or more of the embodiments described herein can be used to deliveran anti-infective agent, such as an antibiotic, anti-viral agent oranti-fungal agent, for the treatment of an ocular infection. They canalso be used to deliver a steroid, for example, hydrocortisone,dexamethasone sodium phosphate or methylprednisolone acetate, for thetreatment of an inflammatory disease of the eye. One or more of theembodiments described herein can be used to deliver a chemotherapeuticor cytotoxic agent, for example, methotrexate, chlorambucil, orcyclosporine, for the treatment of a neoplasm. They can also be used todeliver an anti-inflammatory drug and/or a carbonic anhydrase inhibitorfor the treatment of certain degenerative ocular disorders.

Chronic infections located in a specific tissue and suppressible bylong-term local treatment without developing resistance (e.g., viralinfections) can be treated using one or more of the embodimentsdescribed herein.

The above list of treating drug and treated condition examples aremerely illustrative and do not exclude uses of one or more other drugsin the previous list of example drugs to treat a condition in theprevious list of example conditions.

The devices and systems described herein can be configured for use inveterinary, diagnostic, laboratory, clinical research and development(“clinical R&D”) or other types of environments, as well as use of suchdevices and/or systems in such environments.

While the specification describes particular embodiments of the systems,devices, and methods described herein, those of ordinary skill candevise variations to this subject matter without departing from thespirit and scope of the present disclosure. Thus, the claims are notintended to be limited to the embodiments shown, but are to be accordedthe full scope consistent with the language of the claims, wherereference to an element in the singular is not intended to mean “one andonly one” unless specifically so stated, but rather “one or more.” Allstructural and functional equivalents to the elements of the variousembodiments described throughout this disclosure that are known or latercome to be known to those or ordinary skill in the art are expresslyincorporated herein by reference and are intended to be encompassed bythe claims. Moreover, nothing disclosed herein is intended to bededication to the public regardless of whether such disclosure isexplicitly recited in the claims. No claim elements are to be construedunder the provisions of 35 U.S.C. §112, sixth paragraph, unless theelement is expressly recited using the phrase “means for” or, in thecase of a method claim, the element is recited using the phrase “stepfor.”

What is claimed is:
 1. A method of manufacturing an implantable drugdelivery system including an impedance pump, comprising: forming a firstlayer of a substrate having a pump chamber wall on which an activationelement can be mounted; forming a second layer of the substrate havingan elongate recess connected to a plurality of elongate channels;coupling the first layer to the second layer such that the pump chamberwall is positioned over the elongate recess and such that the elongaterecess and the plurality of elongate channels are covered by the firstlayer; and coupling the activation element to the pump chamber wall. 2.The method of claim 1, wherein the first layer is formed with areservoir, and wherein the first and second layers are coupled togethersuch that the reservoir is in communication with at least one of theplurality of elongate channels.
 3. The method of claim 2, furthercomprising inserting a medicament into the reservoir and sealing thereservoir.
 4. The method of claim 1, wherein the plurality of elongatechannels terminate in two or more openings in the sidewall of thesubstrate, the method further comprising: inserting drug perfusiontubing into the two or more openings; and overmolding the tubing tosecure and seal the tubing to the substrate.
 5. The method of claim 4,further comprising adding adhesive to further secure and seal the tubingto the substrate.
 6. The method of claim 1, wherein the first and secondlayers are formed with a mold having features micromachined thereon. 7.A medicament delivery system, comprising: a substrate; an impedance pumpcoupled to the substrate; and at least one medicament reservoir formedin the substrate and in fluid communication with the impedance pump. 8.The system according to claim 7, further comprising: an activationelement disposed on the impedance pump, wherein activation of theactivation element causes a cross-section of a portion of the impedancepump to decrease.
 9. The system according to claim 8, wherein theactivation element is a magnet.
 10. The system according to claim 7,further comprising: a first tube and a second tube, each coupled to thesubstrate; a first channel in the substrate adapted to provide fluidcommunication between the impedance pump and the first tube; and asecond channel in the substrate adapted to provide fluid communicationbetween the impedance pump and the second tube.
 11. The system accordingto claim 10, wherein a first cross-section of the first channel and asecond cross-section of the second channel are less than a cross-sectionof the impedance pump.
 12. The system according to claim 10, wherein thefirst and second tubes extend laterally from the substrate.
 13. Thesystem according to claim 12, wherein the first and second tubes arecoupled to an interface component.
 14. The system according to claim 12,further comprising a dual lumen tube, wherein the first tube and thesecond tube are in fluid communication with lumens in the dual-lumentube.
 15. The system according to claim 12, wherein portions of thefirst and second tubes are covered by a sheath.
 16. The system accordingto claim 10, wherein the at least one medicament reservoir is in fluidcommunication with the first channel or the second channel.
 17. Thesystem according to claim 7, further comprising a medicament stored inthe at least one medicament reservoir.